CN109562074A - Single-layer sheet compound formulation comprising Telmisartan - Google Patents
Single-layer sheet compound formulation comprising Telmisartan Download PDFInfo
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- CN109562074A CN109562074A CN201680088202.3A CN201680088202A CN109562074A CN 109562074 A CN109562074 A CN 109562074A CN 201680088202 A CN201680088202 A CN 201680088202A CN 109562074 A CN109562074 A CN 109562074A
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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Abstract
The present invention relates to the anti-hypertension compound formulations comprising Telmisartan that can be made into single-layer sheet, specifically, being related to anti-hypertension compound formulation, which is characterized in that are including Telmisartan as active constituent；With in the anti-hypertension compound formulation of the amlodipine as calcium channel blocker or other rescinnamines of the Hydrochioro as diuretics, Telmisartan and the excipient containing aluminium magensium silicate compound and calcium phosphate dibasic anhydrous, bonding agent, disintegrating agent and lubricant are formed together particle, and include Telmisartan of the weight ratio within the range of 1:0.2~0.5: aluminium magensium silicate compound, Telmisartan and other rescinnamines include within the same layer together.Telmisartan anti-hypertension compound formulation of the invention will not lead to the problem of the dissolution of each ingredient even if single-layer sheet is made, and with the original pharmaceuticals-Twynsta piece that ensures safety and validityTMOr Micardis plus pieceTMShow the dissolution identity property and biology equivalence of Telmisartan, to can ensure that safety and validity, in addition, impurity will not be generated, stability is very high, high to the stability of humidity, therefore also have the advantages that can be used in terms of the packaging of tablet PE bottles, PTP a variety of packing methods such as pack, moreover, simply single layer is prepared by direct pressure closing, so also having the effect of reducing preparation expense and time.
Description
Technical field
The present invention relates to the compound formulations comprising Telmisartan that can be made into single-layer sheet.
Background technique
Due to the influence of West Europe formula dietetic life and environment, the population of hypertensive patient increases every year, reaches about 10 at present
Hundred million people, it is contemplated that 1,500,000,000 people will be broken through in 2025.
According to increased hypertensive patient explosive in this way, the market of hypertension therapeutic agent is also sharply developed, current high blood
Pressure pharmaceuticals market occupies about the 10% of world pharmaceuticals market, and market scale reaches about 42,000,000 won.
Current rescinnamine substantially has ACE (angiotensin converting enzyme: Angiotensin-Converting
Enzyme) inhibitor, angiotensin receptor blocker (ARB；Angiotensin Receptor Blockers) and calcium
Channel blocker (CCB；Calcium Channel Blocker) etc..
In addition it is also possible to be used together with the diuretics for promoting sodium ion to be discharged, alleviate cardiovascular contraction.
Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe early stage blocks the formation for causing vasoconstrictive angiotensins, to alleviate cardiovascular contraction；
Angiotensin receptor blocker has the function of interfering angiotensins, to alleviate cardiovascular contraction；Calcium channel blocking
Agent inhibits the inflow of calcium ion, to alleviate cardiovascular contraction；Diuretics is discharge sodium；Inhibition is played by above-mentioned each mode
The effect that blood pressure rises.
Hypertension diagnosis and the international guide (guideline) [JNC-7 report] for the treatment of are pointed out, by Blood Pressure Classification
Standard simplified is four-stage, emphasizes stringent blood pressure management, in particular, hypertensive patient needs to adjust blood pressure and uses two
Kind or more drug.
In general, angiotensin receptor blocker is just formally to show antihypertensive effect after four weeks, it is advantageous to for
And with other kinds of drug, adjust the blood pressure of hypertensive patient since administration initial stage.
In particular, without other with disease when, recommend and the therapy of thiazide diuretic.
It is compound in the market in hypertension pharmaceuticals recently with the trend for recommending above-mentioned two or more drug combination therapies
Agent is more liked than single dose, also occurs the trend for reducing single dose of market and gradually expanding complexing agent market in market scale
(" single dose of hypertension ' complexing agent-' grief and joy is interlocked ", daily magazine newspaper office medicine newspaper, on June 29th, 2012 access http: //
Www.bosa.co.kr/umap/sub.asp? news_pk=185979, on August 13rd, 2012).
Angiotensin receptor blocker (ARB) is Telmisartan (telmisartan), Valsartan (valsartan), difficult to understand
Mei Shatan (olmesartan), Losartan (losartan), Candesartan (candesartan), irbesartan
(irbesartan), eprosartan (eprosartan) etc..
But according to European Society of Cardiology year regular meeting, (Buddhist nun admires in European Society of Cardiology, Germany
It is black) in the TRANSCEND clinical study results delivered, can confirm that Telmisartan is imitated with cardiovascular protection in these ARB drugs
Fruit.
Moreover, result of study discovery recently, compared with other angiotensin receptor blocker, potassemia side effect hair
Raw dangerous low (Park Rae Woong (2012), " Comparison of Hyperkalemic Risk in
Hospitalized Patients Treated with Different Angiotensin Receptor Blockers:A
Retrospective Cohort Study Using a Korean Clinical Research Database”,
American Journal of Cardiovascular Drugs), Telmisartan is by most excellent in existing ARB drug
The evaluation of drug.
Complexing agent comprising Telmisartan is with the Micardis of Boehringer Ingelheim (BOEHRINGER INGELHEIM)(complexing agent of Telmisartan and Hydrochioro) and with company(Telmisartan and amlodipine
Complexing agent) it sells, the very big repercussion by market.
Conventional art about Telmisartan complexing agent is also referred to following patent documents 1 to patent document 2 to understand
(therefore, the full content of patent document 1 to patent document 2 is the document of conventional art, so the content with this specification is closed
And).
Patent document 1 discloses the bilayer tablet of Telmisartan and amlodipine, which includes: in order to from dissolubility
Tablet matrix abrupt release angiotensin II receptor antagonist-Telmisartan and formulation first layer；In order to from disintegration
Or eroding tablet matrix abrupt release calcium channel blocker-amlodipine and the formulation second layer.
Patent document 2 is related to the pharmaceutical composition containing Telmisartan and Hydrochioro, specifically, disclosing bilayer
Telmisartan core is carried out primary coating using containing inertia water-soluble polymer-polyvinylpyrrolidone mixture by tablet,
And second coat is carried out using the mixture of diuretics-Hydrochioro and polyvinylpyrrolidone above it, to have excellent
The dissolution rate of different diuretics, compared with previous commercial preparation, the size and weight of pharmaceutical composition are smaller, and patient takes more
It is easy to add, therefore utilizing status is more excellent in medical industries.
It can confirm from presently commercially available Telmisartan complexing agent and the patent document about above-mentioned Telmisartan complexing agent etc.,
Telmisartan complexing agent is only prepared into bilayer tablet, i.e. dual tablet (double-layer tablet) at present, this is because
In the physiological pH range of the gastrointestinal tract of pH 1 to 7, in order to improve there is the solubility low-down feature in water-soluble system to replace
The solubility of meter Sha Tan uses the highly basic agent such as sodium hydroxide.
The strong alkaline substances such as sodium hydroxide have property, the i.e. hygroscopy of self-dissolving after the moisture in very strong absorption air,
So Telmisartan formulations there will be the case where hygroscopy, telmisartan tablet, will melt behind Kaifeng less than several hours,
To have very big problem in drug keeping stability.
In addition, strong basicity will dissolve out impurity from the second medicinal ingredient except Telmisartan, also preparation can be caused steady
Qualitative problem.
To solve these problems, the researchs such as the preparation method of ingredient except covering Telmisartan have been carried out, but have been existed
Cover ingredient gel-forming characteristic and reduce solution rate other problem (referring to patent document 2 background technique).
(patent document 1) WO Publication 2006/048208 (2006.05.1l.)
(patent document 2) KR trade mark publication 10-1010325Bl (201l.0l.25.)
Summary of the invention
As described above, previous Telmisartan complexing agent is had to using double layers tablet form, this is because there are because
In Telmisartan comprising play the role of solubilizer alkalization ingredient-sodium hydroxide and highly basic agent and generate other rescinnamines
Impurity the problem of and each ingredient dissolution mode issue.
But dual is that the high price such as double compression machine is needed to equip in the preparation, not only yield about 80~90% is low
Yield need 2~3 times of activity duration and compared with single-layer sheet, to ask there are producing cost is very high
Topic.
For this purpose, to solve the above problems, the present invention provides the Telmisartan compound formulation that can be made into single-layer sheet.
The present invention is proposed to solve the problems, such as above-mentioned conventional art, and the present invention provides anti-hypertension compound formulation, special
Sign is,
It is including Telmisartan as active constituent；With
Other rescinnamines of the amlodipine as calcium channel blocker or the Hydrochioro as diuretics
In anti-hypertension compound formulation,
Telmisartan and the excipient containing aluminium magensium silicate compound and calcium phosphate dibasic anhydrous, bonding agent, disintegrating agent, with
And lubricant is formed together particle,
And include Telmisartan of the weight ratio within the range of 1:0.2~0.5: aluminium magensium silicate compound,
Telmisartan and other rescinnamines include within the same layer together.
In addition, the present invention provides anti-hypertension compound formulation, which is characterized in that the dissolution rate and same amount of Telmisartan
TwynstaTMThe dissolution rate of the Telmisartan of piece is peer-level.
In addition, the present invention provides anti-hypertension compound formulation, which is characterized in that the dissolution rate and same amount of Telmisartan
Micardis plusTMThe dissolution rate of the Telmisartan of piece is peer-level.
In addition, the present invention provides anti-hypertension compound formulation, which is characterized in that other in above-mentioned antihypertensive preparation are anti-
Hypertension agent is amlodipine, the Telmisartan and amlodipine in above-mentioned anti-hypertension compound formulation with identical use
Measure the Twynsta of active constituentTMPiece is compared, show biology equivalent horizontal blood level-time graph under area (AUC) and
Highest blood level (Cmax)。
In addition, the present invention provides anti-hypertension compound formulation, which is characterized in that other in above-mentioned antihypertensive preparation are anti-
Hypertension agent is Hydrochioro, and the Telmisartan and Hydrochioro in above-mentioned anti-hypertension compound formulation are lived with having same amount
The Micardis plus of property ingredientTMPiece is compared, and shows area (AUC) under blood level-time graph of biology equivalent horizontal
With highest blood level (Cmax)。
The present invention provide anti-hypertension compound formulation, which is characterized in that the content of above-mentioned calcium phosphate dibasic anhydrous be relative to
0.1~5 weight % of total formulation weight.
The present invention provides anti-hypertension compound formulation, which is characterized in that above-mentioned bonding agent is selected from hydroxypropyl methyl fiber
One or more of element and povidone (povidone), content are 0.05~1.5 weight % relative to total formulation weight.
In addition, the present invention provides anti-hypertension compound formulation, which is characterized in that above-mentioned aluminium magensium silicate compound is inclined silicon
Sour magnalium.
In addition, the present invention provides anti-hypertension compound formulation, which is characterized in that above-mentioned disintegrating agent is selected from the poly- dimension of crosslinking
One or more of ketone, low-substituted hydroxypropyl cellulose and calcium carboxymethylcellulose.
In addition, the present invention provides anti-hypertension compound formulation, which is characterized in that above-mentioned lubricant is selected from collagenous dioxy
One or more of SiClx and sodium stearyl fumarate.
Invention effect
Telmisartan compound formulation of the invention will not lead to the problem of the dissolution of each ingredient even if single-layer sheet is made,
And with the original pharmaceuticals-Twynsta piece that ensures safety and validityTMOr Micardis plus pieceTMMeter Sha is replaced in display
Smooth dissolution identity property and biology equivalence, to can ensure that safety and validity.
In addition, impurity will not be generated, stability is very high, high to the stability of humidity, therefore in terms of the packaging of tablet
Also have the advantages that can be used PE bottles, a variety of packing methods such as PTP packaging.
Moreover, simply single layer is prepared by direct pressure closing, so also having the effect of reducing preparation expense and time.
Detailed description of the invention
Fig. 1 is the photo for indicating result when embodiment and comparative example is placed at room temperature for 7 days under long-term maintaining requirement.
Fig. 2 is the photo for indicating result when embodiment and comparative example is placed at room temperature for 7 days under the conditions of accelerated test.
Specific embodiment
The following detailed description of the present invention.
The present invention provides anti-hypertension compound formulation, which is characterized in that
It is including Telmisartan as active constituent；With
Other rescinnamines of the amlodipine as calcium channel blocker or the Hydrochioro as diuretics
In anti-hypertension compound formulation,
Telmisartan and the excipient containing aluminium magensium silicate compound and calcium phosphate dibasic anhydrous, bonding agent, disintegrating agent, with
And lubricant is formed together particle,
And include Telmisartan of the weight ratio within the range of 1:0.2~0.5: aluminium magensium silicate compound,
Telmisartan and other rescinnamines include within the same layer together.
In particular, Telmisartan and other rescinnamines are not point it is a feature of the present invention that different from previous invention
Not Bao Han different layers, and be included in identical layer.
According to conventional art, if Telmisartan and other rescinnamines are included in identical layer, will exist because replacing rice
The strong basicity of the solubilizer of Sha Tan and lead to the problem of impurity or tablet self-dissolving due to hygroscopy.
For such problems, conventional art is that have the first layer comprising Telmisartan by preparation and resist comprising other
The tablet of the second layer of hypertension agent is solved by having the multilayer tablet of the tablet of more than two layers.
But as described above, dual needs the equipment of high price, yield is low, and the process time is long, so there are productivity drops
The problem of low, producing cost increases considerably.
For this purpose, the inventors of the present application found that the Telmisartan for being dissolved in strong basicity solubilizer is adsorbed on alumina silicate
When salt compound, even if single-layer sheet is made, impurity or hygroscopy problem etc. will not be caused, thus complete the present invention.
The above-mentioned identical layer that is included in refers to Telmisartan and other rescinnamines not in the form of core and its overlay film
It is separated in tablet, refers to that Telmisartan and other rescinnamines do not wait multilayer tablets form fractionation (about double with dual
The patent document 1 that the conventional art and meaning of weight piece are referred to above-mentioned conventional art understands to patent document 2).
It is, including that identical layer refers to that substantial on the single layer face of tablet (substantially) does not distinguish work
The region of Telmisartan is only existed for principal component and the region of other rescinnamines is only existed as principal component, but specified
Region exists simultaneously Telmisartan and other rescinnamines.
In particular, the invention is characterized in that Telmisartan and other rescinnamines are included in identical layer simultaneously, but it is real
It can be further equipped in matter and include the layer of Telmisartan as principal component or include other rescinnamines as principal component
Layer does not repel these (it is, it is the Telmisartan that cannot achieve with conventional art and other that feature of the invention, which is,
The layer that rescinnamine includes simultaneously does not repel and further includes other extra plays).
It is because molten that other anti-hypertension ingredients that identical layer cannot be included in the past can contain together with Telmisartan
Solution is adsorbed in aluminium silicate compounds in the Telmisartan of basifier.
For this purpose, in the present invention, by the various excipient comprising aluminium magensium silicate compound, disintegrating agent etc. and Telmisartan one
Play mixing and absorption.
The method that aluminium magensium silicate compound and excipient mix can be enumerated for example, being added to high-speed joint machine or fluidisation
Bed granulating and drying machine, the method with Telmisartan high-speed joint etc., but it is not necessarily defined in this, the art has logical
Naturally clear adsorption method is in the range for not damaging the object of the invention to the personnel (hereinafter referred to as " those skilled in the art ") of Chang Zhishi
It is interior to use in non-limiting manner.
Above-mentioned " Telmisartan " includes the Telmisartan of all pharmacologically active constituents itself and pharmaceutically allows
Telmisartan salt or the isomers of Telmisartan etc..
Above-mentioned " amlodipine " includes the amlodipine of all pharmacologically active constituents itself and can pharmaceutically permit
Perhaps salt or the isomers of amlodipine of amlodipine etc..
Above-mentioned " aluminium magensium silicate compound " is by silica (SiO2), aluminium oxide (Al2O3), magnesia (MgO) mixing
The compound of formation, including multiple existing for content ratio between all arrangement architectures according between each ingredient and each ingredient
The compound of type.Typically, aluminum magnesium silicate (magnesium aluminosilicate), magnesium aluminometasilicate
(magnesium aluminometasilicate), zeopan (magnesium aluminum silicate) etc..Only
It is that in the present invention, above-mentioned aluminium magensium silicate compound is preferably magnesium aluminometasilicate.These further specific definition and content can
Reference [USP34 NF 29], United States Pharmacopeia (The United States Phannacopoeia), 2011.08.01.,
Pp.1568-1570 understands that therefore, above-mentioned document includes as a part of present specification.
Above-mentioned aluminium magensium silicate compound can be used magnesium aluminometasilicate, preferably Telmisartan: aluminium magensium silicate compound=
Weight ratio within the range of 1:0.2~0.5 includes.When the amount of aluminium magensium silicate compound is more than that above range is excessive, although
Have the advantages that easy absorption Telmisartan solution and keeping safety increases, but tablet size is excessive, it is very not square when taking
Just, and dissolution rate is reduced；In contrast, it when the amount of aluminium magensium silicate compound is more than that above range is very few, is difficult to realize
The increase of preliminary solubility and the absorption of Telmisartan solution not only prepare difficulty, but also replace because being dissolved in the unadsorbed of basifier
Meter Sha Tan and generate keeping stability the problems such as.
In particular, it is a feature of the present invention that the dissolution rate of Telmisartan and the Twynsta of same amountTMPiece replaces meter Sha
The Micardis plus of smooth dissolution rate or same amountTMThe dissolution rate of the Telmisartan of piece has peer-level, for this purpose, will
The amount of aluminium magensium silicate compound relative to Telmisartan must be adjusted within the above range.For example, relative to Telmisartan
The amount of aluminium magensium silicate compound when being more than that 0.5 weight ratio is more, even if being judged as common dissolving out capability, there is no problem, also difficult
To ensure to dissolve out identity property.
Moreover, it is a feature of the present invention that other rescinnamines in above-mentioned anti-hypertension compound formulation for A Moluo
Usually, the Telmisartan in above-mentioned anti-hypertension compound formulation and amlodipine with same amount active constituent
TwynstaTMPiece is compared, and shows area (AUC) and highest blood level under blood level-time graph of biology equivalent horizontal
(Cmax)；When other rescinnamines in above-mentioned anti-hypertension compound formulation are Hydrochioro, above-mentioned anti-hypertension compound formulation
Interior Telmisartan and Hydrochioro and the Micardis plus with same amount active constituentTMPiece is compared, and shows biology
Area (AUC) and highest blood level (C under blood level-time graph of equivalent horizontalmax), therefore, not only to consider molten
Out, and to consider the blood level after absorbing, it is appropriate to adjust drug release degree.
Wherein, according to pharmaceuticals consistency criterion, judge under blood level-time graph in area (AUC) and highest blood
Concentration (Cmax) whether show biology equivalent horizontal.For example, according to pharmacists's relevant laws and regulations collection pharmaceuticals Consistency test standard
Biology equivalence trial, will be dense in area (AUC) under blood level-time graph of comparison medicine and investigational agent and highest blood
Spend (Cmax) logarithmic transformation and statistical disposition are carried out, at this point, if 90% confidence interval of the difference of the average value of logarithmic transformation
In, two projects all meet 0.8~log of log l.25 within when, it is believed that pharmaceuticals Consistency test be it is identical.Only, according to
Lively exception regulation, 1) if the difference of the average value of the logarithmic transformation of the comparative evaluation item value of comparison medicine and investigational agent is log
0.9 to log l.11 within when, 2) according to pharmaceuticals consistency criterion implement compare dissolution test when, defined all identical
Under the conditions of all to it is corresponding when it is determined that equivalent.
The content of above-mentioned calcium phosphate dibasic anhydrous is preferably 0.1~5 weight % relative to total formulation weight.Anhydrous phosphoric acid hydrogen
Calcium is conducive to formulation flows, and even more raising preparation takes care of safety, when less than 0.1 weight %, these low efforts, and work as
When more than 5 weight %, tablet is made to harden to necessity or more, had an adverse effect to disintegration and dissolution, so not preferably.Especially
It is, when the usage amount of the aluminium magensium silicate compound relative to Telmisartan is few, because basifier dissolves the hygroscopy of Telmisartan
And some reductions of stability are taken care of, when addition calcium phosphate dibasic anhydrous in right amount, it can solve these hygroscopy and lead to the problem of.This
A little more detailed understandings are can be carried out by aftermentioned most preferred embodiment.
Although above-mentioned bonding agent can be without limitation using widely used bonding agent in pharmacy, it is contemplated that molten
, it is preferable to use the hydrophily bonding agent not had an impact to pH in the hygroscopy of the Telmisartan of basifier the problems such as.To this measure
Example is selected from one or more of hydroxypropyl methyl cellulose and povidone.Above-mentioned bonding agent is strong to the combination of telmisartan granules
Degree has an impact, and therefore, dissolution rate and keeping safety to Telmisartan also have an impact.Therefore, above-mentioned bonding agent contains
0.05~1.5 weight % of the amount preferably relative to total formulation weight.When less than 0.05 weight %, it is not easy to particle is formed,
Or the bond strength of particle is weak, also generates side effect to keeping safety；And when more than 1.5 weight %, to Telmisartan
Dissolution generate side effect.
Although above-mentioned disintegrating agent can be without limitation using widely used disintegrating agent in pharmacy, it is contemplated that molten
Extracting rate etc., preferably selects disintegrating agent appropriate, this is exemplified as selected from crospovidone, low-substituted hydroxypropyl cellulose and
One or more of calcium carboxymethylcellulose.Furthermore, it is contemplated that dissolution rate etc., the content of above-mentioned disintegrating agent is preferably relative to packet
Within 10~30 weight % ranges of the particle total weight containing Telmisartan.
Above-mentioned lubricant can be exemplified as this without limitation using widely used lubricant in pharmacy selected from glue
One or more of matter silica and sodium stearyl fumarate.
In addition, the present invention other than Telmisartan, amlodipine and Hydrochioro, can also further include it
It is his rescinnamine, known such as Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, angiotensin receptor blocker, calcium channel blocker and diuretics
Rescinnamine.
The type of above-mentioned Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe is not particularly limited, and can enumerate as unrestricted example, captopril
(captopril), enalapril (enalapril), quinapril (quinapril), Ramipril (ramipril), Lai Nuopu
Benefit (lisinopril), benazepil (benazepril), fosinopril (fosinopril).
The type of above-mentioned angiotensin receptor blocker (ARB) is not particularly limited, can as unrestricted example
It enumerates, Valsartan (valsartan), Olmesartan (olmesartan), Losartan (losartan), Candesartan
(candesartan), irbesartan (irbesartan), eprosartan (eprosartan).
The type of above-mentioned calcium channel blocker (CCB) is not particularly limited, and can enumerate as unrestricted example, nitre benzene
Horizon, Nisoldipine, felodipine, reaches Lip river Horizon, fluorine Flordipine at NimodipineLacidipine, according to drawing
Horizon, Niguldipine, niludipine, sand ground difficult to understand be flat, Elgodipine, Riodipine, Nilvadipine, Lemildipine
Nitrendipine, nicardipine, Verapamil, diltiazem and flunarizine.
The type of above-mentioned diuretics is not particularly limited, and can enumerate as unrestricted example, chlorothiazide, frusemide
(furosemide), bumetanide (bumetanide), spirolactone (spironolactone), triamterene
(triamterene)。
Below by the most preferred embodiment present invention detailed further.Following most preferred embodiment is just for the sake of detailed
Describe bright invention in detail, purpose is not thus to limit interest field.
Embodiment
Embodiment 1: the compound formulation of Telmisartan and amlodipine
(1) preparation of telmisartan granules
Sodium hydroxide is dissolved in the sodium hydrate aqueous solution of Purified Water, ethyl alcohol is added, hydroxypropyl methyl fiber is added
After element dissolution, it is slowly added into Telmisartan dissolution, preparation combines liquid.
Calcium phosphate dibasic anhydrous, magnesium aluminometasilicate, mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, crosslinking is poly-
Dimension ketone, calcium carboxymethylcellulose, collagenous silica are added to high-speed joint machine, with mixed at high speed.
Above-mentioned obtained be added in said mixture in conjunction with liquid is combined.
After drying above-mentioned combination and being pelletized with 25 sieve meshes (mesh), in above-mentioned granulation object benzene sulfonic acid ammonia chlorine is added
Flat, crospovidone, mannitol, calcium carboxymethylcellulose are mixed, as the collagenous silica of lubricant addition and firmly
Acyl fumaric acid sodium is mixed simultaneously tabletting, and tablet is finally made.
Blending constituent and ratio are as described in Table 1.
[table 1]
(2) preparation of Amlodipine Besylate Tablet mixture
Amlodipine Besylate Tablet, crospovidone, mannitol and calcium carboxymethylcellulose are added as described in Table 2
Enter to mixing machine and is mixed.
[table 2]
(3) preparation of mix lubricant and tablet
By the collagenous silica of above-mentioned telmisartan granules and Amlodipine Besylate Tablet mixture and 10mg and
After the lubricant of the sodium stearyl fumarate of 14.0mg finally mixes, tabletting is carried out using tablet press machine.
Embodiment 2: the complexing agent of Telmisartan and Hydrochioro
(1) preparation of telmisartan granules
It is identical as 1 use of above-described embodiment other than using the mannitol of 156.7mg, the crospovidone of 16.8mg
Prescription and method preparation.
(2) preparation of Hydrochioro particle
Povidone is dissolved in Purified Water, is made and combines liquid.
Hydrochioro, mannitol, calcium carboxymethylcellulose and crospovidone are added to high-speed joint machine to mix
It closes, and above-mentioned combination liquid obtained is added and is combined.
After drying above-mentioned combination and being pelletized with 25 sieve meshes (mesh), sodium stearyl fumarate is added, is mixed.
[table 3]
(3) preparation of mix lubricant and tablet
After above-mentioned telmisartan granules and Hydrochioro particle are mixed, collagenous silica and 14.0mg with 10mg
Sodium stearyl fumarate lubricant finally mix after, utilize tablet press machine carry out tabletting.
Comparative example: comparison medicine
Comparative example 1: the complexing agent of Telmisartan and Amlodipine Besylate Tablet
Just in commercially available Twynsta piece 80/5mgTM(preparation/import: South Korea's Boehringer Ingelheim, the benzene sulfonic acid of 13.87mg
Amlodipine, the Telmisartan of 40mg)
Comparative example 2: the complexing agent of Telmisartan and Hydrochioro
Just in commercially available Micardis plus piece 80/12.5mgTM(preparation/import: South Korea's Boehringer Ingelheim, 12.5mg
Hydrochioro, the Telmisartan of 40mg)
Experimental example
1, compare dissolution test
(1) experiment condition is dissolved out
Dissolution fluid: pH1.2 liquid (the 1st liquid of slaking test method in great Han pharmacopeia ordinary test method)
PH4.0 liquid (food drug Room bulletin 2011-57 pH4.0 acetate buffer)
PH6.8 liquid (the 2nd liquid of slaking test method in great Han pharmacopeia ordinary test method)
Aqueous (Purified Water)
Leaching temperature: 37 DEG C
The rotation speed of paddle: 50rpm
With above-mentioned experiment condition, 6 each to detectable substance, at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 points
Clock, 90 minutes, (liquid of pH1.2 is 120 minutes, and the liquid of pH1.4 is 180 minutes, the liquid and water of pH6.8 within 120 minutes, 180 minutes
Until being 45 minutes) when take dissolution fluid, detection liquid is obtained by filtration.In addition, the accurate Telmisartan reference substance for weighing 89mg and
The Hydrochioro of 14mg is dissolved in the sodium hydroxide solution of 0.1mol/L, and methanol is added, and the solution of 100ml is made.Take out 10ml
The solution, the solution of 100ml is made with dissolution fluid, in this, as titer.
Detector: UV, visible light extinction photometer (measurement wavelength: 270nm)
Mobile phase: pH6.0 phosphate buffer: acetonitrile=50:50
- pH6.0 phosphate buffer: by the disodium hydrogen phosphate 12 of the biphosphate sodium-hydrate of 7.87g and 2.86g
Hydrate is added to the water dissolution, and the solution of 1000ml is made
Column: C18,4.6 × 150mm, 5 μm or the column that is equal with this
Flow velocity: 1ml/min
Column temperature: 35 DEG C
Sample volume: 10 μ l
(2) comparison of (investigational agent) vs. of embodiment 1 comparative example 1 (comparison medicine) dissolves out result
Following table 5 indicates the dissolution rate of the Amlodipine Besylate Tablet of embodiment 1 and comparative example 1.
[table 5]
Following table 6 indicates the dissolution rate of the Telmisartan of embodiment 1 and comparative example 1.
[table 6]
Using above-mentioned dissolution end value as foundation, according to " the pharmaceuticals consistency of (the Korean foods pharmaceuticals safe place) KFDA
Testing standard (the safe place bulletin of food pharmaceuticals the 2014-188th, 2014-11-24) ", passes through pharmaceuticals Consistency test
Such as the similarity factor (f of following mathematical expressions 1 in (comparing dissolution test) regulation2) be compared, it is equivalent that dissolution is compared in judgement.
[numerical expression 1]
The judging result of each liquid is as shown in table 7.
[table 7]
(3) comparison of (investigational agent) vs. of embodiment 2 comparative example 2 (comparison medicine) dissolves out result
Following table 8 indicates the comparison dissolution rate of the Hydrochioro of embodiment 2 and comparative example 2.
[table 8]
Following table 9 indicates the comparison dissolution rate of the Telmisartan of embodiment 2 and comparative example 2.
[table 9]
Using above-mentioned dissolution end value as foundation, according to " the pharmaceuticals consistency of (the Korean foods pharmaceuticals safe place) KFDA
Testing standard (the safe place bulletin of food pharmaceuticals the 2014-188th, 2014-11-24) ", passes through pharmaceuticals Consistency test
Such as the similarity factor (f of above-mentioned mathematical expression 1 in (comparing dissolution test) regulation2) be compared, it is equivalent that dissolution is compared in judgement.
The judging result of each liquid is as shown in table 10.
[table 10]
2, biology equivalence trial
(1) with Twynsta piece 80/5mgTMThe identity property of (comparative example 1) compares
Positive ground hospital clinical research center by biology equivalence trial volunteer recruiting bulletin (2014.11.07~
2014.11.15), adult healthy volunteers 72 of full 19 years old or more are recruited, according to Korean foods pharmaceuticals safe place KFDA's
The 17th article of " pharmaceuticals Consistency test standard " (the safe place bulletin of food pharmaceuticals the 2014-150th, 2014.09.02), into
Row evaluation.It is, the item compared for the biology equivalence between evaluation test medicine and comparison medicine is, from blood plasma Chinese medicine
Area (AUCt), highest blood level (C under the calculated blood level-time graph of object concentration time curvemax).In addition,
Using the statistical disposition of biology equivalence trial with program (K-BE TEST 2007.1.10 editions), each parameter is become for log
Value is changed, dispersion analysis is carried out at significance (α)=0.05, identifies sequential effects between group, find out comparison medicine and investigational agent
90% confidence interval of the difference of the average value of log transformation.
[area (AUC under blood level-time graph of amlodipinet) identity property identification]
Each subjects person converts AUC for the log of amlodipine AmlodipinetThe analysis of variance table and system of value
Meter qualification result, shown in table 11.
Group or order (Group or Sequence), in the F value (F value) of subject/group (Subject/Group),
Show notable difference, and drug (Drug) in the F value (F value) in stage (Period), does not show notable difference.
The log of comparison medicine and investigational agent converts 90% confidence interval of the difference of average value from 0.9927 to 1.0461, therefore
Meet " pharmaceuticals Consistency test standard " (food pharmaceuticals peace of 0.8 to 1.25 Korean foods pharmaceuticals safe place KFDA
Full place bulletin the 2014-150th, 2014.09.02) the 17th article 2.
From result above it can be proved that two preparations are in assessment item AUCtBiology is equivalent.
[table 11]
[highest blood level (the C about amlodipinemax) identity property identification]
Object is respectively tested, converts C for the log of amlodipine AmlodipinemaxThe analysis of variance table and statistics mirror of value
Determine as a result, shown in table 12.
In the F value (F value) of subject/group (Subject/Group), display notable difference, and group or order
(Group or Sequence), drug (Drug) in the F value (F value) in stage (Period), do not show notable difference.
The log of comparison medicine and investigational agent converts 90% confidence interval of the difference of average value from 0.9798 to 1.0470, therefore
Meet " pharmaceuticals Consistency test standard " (food pharmaceuticals peace of 0.8 to 1.25 Korean foods pharmaceuticals safe place KFDA
Full place bulletin the 2014-150th, 2014.09.02) the 17th article 2.
From result above it can be proved that two preparations are in assessment item CmaxBiology is equivalent.
[table 12]
[area (AUC under blood level-time graph of Telmisartant) identity property identification]
Each subjects person converts AUC for the log of Telmisartan TelmisartantThe analysis of variance table and statistics of value
Qualification result, shown in table 13.
In the F value (F value) of subject/group (Subject/Group), display notable difference, and group or order
(Group or Sequence), drug (Drug) in the F value (F value) in stage (Period), do not show notable difference.
The log of comparison medicine and investigational agent converts 90% confidence interval of the difference of average value from 0.9229 to 1.0458, therefore
Meet " pharmaceuticals Consistency test standard " (food pharmaceuticals peace of 0.8 to 1.25 Korean foods pharmaceuticals safe place KFDA
Full place bulletin the 2014-150th, 2014.09.02) the 17th article 2.
From result above it can be proved that two preparations are in assessment item AUCtBiology is equivalent.
[table 13]
[highest blood level (the C about Telmisartanmax) identity property identification]
Each subjects person converts C for the log of Telmisartan TelmisartanmaxThe analysis of variance table and statistics of value
Qualification result, shown in table 14.
In the F value (F value) of subject/group (Subject/Group), display notable difference, and group or order
(Group or Sequence), drug (Drug) in the F value (F value) in stage (Period), do not show notable difference.
The log of comparison medicine and investigational agent converts 90% confidence interval of the difference of average value from 0.8405 to 1.1372, therefore
Meet " pharmaceuticals Consistency test standard " (food pharmaceuticals peace of 0.8 to 1.25 Korean foods pharmaceuticals safe place KFDA
Full place bulletin the 2014-150th, 2014.09.02) the 17th article 2.
From result above it can be proved that two preparations are in assessment item CmaxBiology is equivalent.
[table 14]
(2) with Micardis plus piece 80/12.5mgTMThe identity property of (comparative example 2) compares
Benevolence mountain city hospital, medical treatment financial group by the volunteer recruiting of biology equivalence trial bulletin (2015.11.06~
2015.11.27), the adult healthy volunteers 76 (being all male) for recruiting full 19 years old or more are pacified according to Korean foods pharmaceuticals
" pharmaceuticals Consistency test standard " (the safe place bulletin of food pharmaceuticals the 2014-150th, 2014.09.02) of full place KFDA
It 17th article, is evaluated.It is, the item compared for the biology equivalence between evaluation test medicine and comparison medicine is,
From area (AUC under the calculated blood level-time graph of blood plasma drug concentration-time grapht), highest blood level
(Cmax).In addition, using the statistical disposition of biology equivalence trial with program (K-BE TEST 2007.1.10 editions), by each ginseng
Number is directed to log transformed value, carries out dispersion analysis at significance (α)=0.05, identifies sequential effects between group, find out comparison medicine
With 90% confidence interval of the difference of the log of the investigational agent average value converted.
[area (AUC under blood level-time graph of Hydrochiorot) identity property identification]
The log of subjects person converts AUCtThe analysis of variance table and statistics qualification result of value, shown in table 15.From the statistics
For processing result it is found that in the span order effect identification of significance (α)=0.05, F value is less than the limitation of F analytical table
Value, confirmation cross matching correctly carry out.In addition, 90% confidence interval of the difference of the log of comparison medicine and investigational agent transformation average value
From log0.9484 to log0.9963, therefore meet the biology equivalence margin of log0.8 to log1.25.
[table 15]
[highest blood level (the C of Hydrochioromax) identity property identification]
The log of subjects person converts CmaxThe analysis of variance table and statistics qualification result of value, shown in table 16.From the statistics
For processing result it is found that in the span order effect identification of significance (α)=0.05, F value is less than the limitation of F analytical table
Value, confirmation cross matching correctly carry out.In addition, 90% confidence interval of the difference of the log of comparison medicine and investigational agent transformation average value
From log0.9514 to log1.0469, therefore meet the biology equivalence margin of log0.8 to log1.25.
[table 16]
[area (AUC under blood level-time graph of Telmisartant) identity property identification]
The log of subjects person converts AUCtThe analysis of variance table and statistics qualification result of value, shown in table 17.From the statistics
For processing result it is found that in the span order effect identification of significance (α)=0.05, F value is less than the limitation of F analytical table
Value, confirmation cross matching correctly carry out.In addition, 90% confidence interval of the difference of the log of comparison medicine and investigational agent transformation average value
From log0.9153 to log1.0112, therefore meet the biology equivalence margin of log0.8 to log1.25.
[table 17]
[highest blood level (the C of Telmisartanmax) identity property identification]
The log of subjects person converts CmaxThe analysis of variance table and statistics qualification result of value, shown in table 18.From the statistics
For processing result it is found that in the span order effect identification of significance (α)=0.05, F value is less than the limitation of F analytical table
Value, confirmation cross matching correctly carry out.In addition, 90% confidence interval of the difference of the log of comparison medicine and investigational agent transformation average value
From log0.8536 to log1.0976, therefore meet the biology equivalence margin of log0.8 to log1.25.
[table 18]
3, impurity is tested
(1) about embodiment 1
[experimental method]
Detect liquid: by two panels, the medicine is added in the flask of 100mL, and 0.1N NaOH 5mL is added, rocks disintegration.Disintegration
Afterwards, 80mL methanol is added, is ultrasonically treated 10 minutes, rocks 30 minutes and extracts.After temperature reaches room temperature, 100mL is made with methanol
Solution.Liquid 10mL is taken out, with diluted to 50mL, detection liquid is made.
Titer: precision weighs the Telmisartan of 160mg and the Amlodipine Besylate Tablet of 28mg, is added to the burning of 100mL
In bottle, the sodium hydrate methanol solution (methanolic solution of sodium hydroxide) that 0.005M is added is molten
Solution.Liquid 10mL is taken out, with diluted to 50mL, detection liquid is made.
Dilution Buffer:Solution=1:1
- Buffer: after the ammonium dihydrogen phosphate of 2.0g is dissolved in the water of 1L, with the solution of phosphoric acid adjustment pH3.0.
- Solution:Acetonitrile:Methanol=:1:1
Detector: UV, visible light extinction photometer (Telmisartan (Telmisartan): 298nm, Amlodipine Besylate Tablet
(Amlodipine besylate): 237nm)
Column: C18,4.6 × 150mm, 5 μm or the column that is equal with this
Flow velocity: 1ml/min
Column temperature: 40 DEG C
Sample volume: 10 μ l
About embodiment 1, accelerated (40 DEG C, 75%RH) keepings, HDPE bottles (bottle) packagings, the experiment knot of impurity
Fruit is as shown in following tables 19.
[table 19]
About embodiment 1, accelerated bag (Alu-bag) packaging of (40 DEG C, 75%RH) keepings, aluminium material, impurity
Experimental result is as shown in following tables 20.
[table 20]
(2) about embodiment 2
About embodiment 2, according to United States Pharmacopeia Telmisartan and hydrochlorothiazide tablets (USP, Telmisartan and
Hydrochlorothiazide tablets) item, accelerated (40 DEG C, 75%RH) keepings, high-density polyethylene bottle (HDPE
Bottle it) packs, implements the experiment of impurity.
As a result as shown in following tables 13.
[table 21]
Accelerated bag (Alu-bag) packaging of (40 DEG C, 75%RH) keepings, aluminium material, the experimental result of impurity is as follows
It states shown in table 14.
[table 22]
4, hygroscopy is tested
By embodiment 1 and comparative example 1 to 3 under long-term maintaining requirement and acceleration environment, carry out respective hygroscopy improve with
No experiment.
Fig. 1 is result when indicating to be placed at room temperature for for 7 days under long-term maintaining requirement.It can confirm from Fig. 1, in keeping item for a long time
Under part.Comparative example 1,2 is to start to melt within two days, and by 7 days, also there is no hygroscopy under open environment for embodiment 1
The phenomenon that dissolution of caused tablet.
Fig. 2 is result when indicating the open placement in 7 days under the conditions of accelerated test.It can confirm from Fig. 2, in accelerated test item
Under part.Comparative example 1,2 is to start to melt within one day, and by 7 days, also there is no hygroscopy under open environment for embodiment 1
The phenomenon that dissolution of caused tablet.
Claims (10)
1. a kind of anti-hypertension compound formulation, which is characterized in that including Telmisartan as active constituent；With as calcium channel
The anti-hypertension compound formulation of other rescinnamines of the amlodipine of retarding agent or the Hydrochioro as diuretics
In, Telmisartan and the excipient containing aluminium magensium silicate compound and calcium phosphate dibasic anhydrous, bonding agent, disintegrating agent, Yi Jirun
Lubrication prescription is formed together particle, and includes Telmisartan of the weight ratio within the range of 1:0.2~0.5: aluminium magensium silicate compound,
Telmisartan and other rescinnamines include within the same layer together.
2. anti-hypertension compound formulation according to claim 1, which is characterized in that the dissolution rate of Telmisartan and identical use
The Twynsta of amountTMThe dissolution rate of the Telmisartan of piece is peer-level.
3. anti-hypertension compound formulation according to claim 1, which is characterized in that the dissolution rate of Telmisartan and identical use
The Micardis plus of amountTMThe dissolution rate of the Telmisartan of piece is peer-level.
4. anti-hypertension compound formulation according to claim 1, which is characterized in that other in the antihypertensive preparation
Rescinnamine is amlodipine, the Telmisartan and amlodipine in the anti-hypertension compound formulation, and with phase
With the Twynsta of dosage active constituentTMPiece is compared, and shows area under blood level-time graph of biology equivalent horizontal
(AUC) and highest blood level (Cmax)。
5. anti-hypertension compound formulation according to claim 1, which is characterized in that other in the antihypertensive preparation
Rescinnamine is Hydrochioro, the Telmisartan and Hydrochioro in the anti-hypertension compound formulation, and with identical use
Measure the Micardis plus of active constituentTMPiece is compared, and shows area under blood level-time graph of biology equivalent horizontal
(AUC) and highest blood level (Cmax)。
6. anti-hypertension compound formulation according to claim 1, which is characterized in that the content of the calcium phosphate dibasic anhydrous is
0.1~5 weight % relative to total formulation weight.
7. anti-hypertension compound formulation according to claim 1, which is characterized in that the bonding agent is selected from hydroxypropyl first
One or more of base cellulose and povidone, the content of the bonding agent are 0.05~1.5 weight relative to total formulation weight
Measure %.
8. anti-hypertension compound formulation according to claim 1, which is characterized in that the aluminium magensium silicate compound is inclined
Aluminum magnesium silicate.
9. anti-hypertension compound formulation according to claim 1, which is characterized in that the disintegrating agent is selected from the poly- dimension of crosslinking
One or more of ketone, low-substituted hydroxypropyl cellulose and calcium carboxymethylcellulose.
10. anti-hypertension compound formulation according to claim 1, which is characterized in that the lubricant is selected from collagenous
One or more of silica and sodium stearyl fumarate.
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| PCT/KR2016/008842 WO2018030559A1 (en) | 2016-08-11 | 2016-08-11 | Single-layer-tablet combined preparation containing telmisartan |
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| CN112569241A (en) * | 2019-09-27 | 2021-03-30 | 武汉武药科技有限公司 | Telmisartan and hydrochlorothiazide double-layer tablet and preparation method thereof |
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| KR20190028533A (en) | 2019-03-18 |
| WO2018030559A1 (en) | 2018-02-15 |
| KR102274147B9 (en) | 2022-03-28 |
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Application publication date: 20190402 |